Transcript I. Introduction to class

Chapter 24
THE IMMUNE SYSTEM
Introduction
Resistance: Ability to ward off disease.
 Nonspecific
Resistance: Defenses that protect
against all pathogens.
 Specific
Resistance: Protection against specific
pathogens.
Susceptibility: Vulnerability or lack of
resistance.
Protection Against Invading Pathogens
1. First Line of Defense: Non-specific natural
barriers which restrict entry of pathogen.
Examples: Skin and mucous membranes.
2. Second Line of Defense: Non-specific defenses that
provide rapid local response to pathogen after it
has entered body.
Examples: Fever, phagocytes (macrophages and
neutrophils), inflammation, and interferon.
3. Third line of defense: Antigen-specific immune
responses, specifically target and attack invaders
that get past first two lines of defense.
Examples: Antibodies and lymphocytes.
Defenses Against Infection
First Line of Defense: Skin is an Effective Barrier
Against Infection by Most Pathogens
Second Line of Defense: Interferon is Nonspecific
Inhibitor of Viral Infection
Inflammation is a Nonspecific Defense
1. Damaged cells release chemical signals: Histamine
and other molecules.
2. Local response to chemical signals:





Increase in local blood flow and vascular permeability
Redness
Heat
Swelling
Pain
3. Phagocytic white blood cells come into area:
Engulf bacteria, dead cell parts, and other
microbes.
4. Tissue heals
Inflammatory Response: Nonspecific Defenses
Third Line of Defense: The Immune
Response
Immunity: “Free from burden”. Ability of
an organism to recognize and defend itself
against specific pathogens or antigens.
Immune Response: Involves production of
antibodies and generation of specialized
lymphocytes against specific antigens.
Antigen: Molecules from a pathogen or
foreign organism that provoke a specific
immune response.
Lymphatic and Immune System
Components: Lymph, lymphatic vessels, bone
marrow, thymus, spleen, and lymph nodes.
Functions:
 Defends
against infection: bacteria, fungi, viruses, etc.
 Destruction of cancer and foreign cells.
 Synthesis of antibodies and other immune molecules.
 Synthesis of white blood cells.
Homeostatic Role:
 Returns
fluid and proteins that have leaked from
blood capillaries into tissues.


Up to 4 liters of fluid every day.
Fluid returned near heart/venae cavae.
Lymphatic System
The Immune Response Destroys Specific
Invaders
Antigen: Molecule that elicits an immune response.
“Antibody generating”.
 Microbial
antigens: Viral capsid, bacterial call wall, etc.
 Nonmicrobial
antigens: Pollen, latex, food, etc.
Antibody: Protein found in blood plasma that
attaches to antigen and helps counteract its effects.
Vaccination or Immunization: Process in which
harmless forms of antigen or pathogen are
introduced into body to provoke an immune
response.
Lymphocytes Mount a Dual Immune Defense
1. Cell Mediated Immunity
 Immunity that requires cell to cell contact.
 Carried out by T cells:
 Develop
in the thymus.
 Only recognize antigen associated with self-protein.
 T cytotoxic cells: Important in defense against:


Cancer cells
Self cells infected with fungi, viruses, protozoans, and bacteria.
T
helper cells: Play a central role in immunity.
Act indirectly by controlling the immune functions of
other cells:



Increased antibody production by B cells.
Increased phagocytosis by macrophages.
Increased killing of foreign and cancer cells.
Development of T and B Lymphocytes
T helper cells play a central role in immunity
Lymphocytes Mount a Dual Immune Defense
2. Humoral (Antibody Mediated) Immunity
 Antibodies



Blood
Lymph
Interstitial fluid
 Antibodies

are found in our body fluids:
are produced by B cells.
B cells develop in bone marrow.
Antibodies are specific molecules that circulate through
out our body and attach to foreign antigens, marking
them for destruction.
 Foreign antigen does not have to be associated with a self
antigen to be recognized.
 Antibodies can be passed from one individual to another:



Mother-child: Mother’s antibodies cross placenta. Also found in
breast milk.
Serum: Snake bite antivenom.
Antibodies are Protein Molecules that
Recognize Specific Foreign Antigens
Antibodies Help Eliminate Foreign Antigens
Acquired Immunodeficiency
Syndrome (AIDS)
History
 1950s:
Blood samples from Africa have HIV
antibodies.
 1976: First known AIDS patient died.
 1981: First reports of “Acquired Immunodeficiency Syndrome” at UCLA.
 1983: Virus first isolated in France.
 1984: Virus isolated in the U.S.
 1985: Development and implementation of
antibody test to screen blood donors.
History (Continued)
 1986:
Virus named Human Immunodeficiency
Virus (HIV-1).
Related virus (HIV-2) identified.
 1992: AIDS becomes the leading cause of death
among adults ages 25-44 in the U.S.
 1998: AIDS death rates start to decline in U.S. due
to the introduction of new drug cocktails.
 1999: Over 33 million HIV infected individuals.
Another 16 million have already died from AIDS.
 2000: World Health Organization predicts up to
40 million infected individuals.
AIDS Becomes a Leading Cause of Death
Among People Aged 25-44 years in U.S.
40
35
30
25
AIDS
Accidents
Cancer
Homicide
20
15
10
5
0
1982
1986
1990
1994
Deaths per 100,000 people aged 25-44 years
People Living with HIV/AIDS by End of 1999
North America
920,000
Western Europe
520,000
East Europe & Central Asia
360,000
East Asia & Pacific
530,000
North Africa &
Middle East
220,000
Latin America
1.3 million
South/South East Asia
6.0 million
Sub-Saharan Africa
23.3 million
Total: 33.6 million people
Australia &
New Zealand
12,000
Transmission of HIV (Worldwide)
1. Sexual contact with infected individual: All forms of
sexual intercourse (homosexual and heterosexual).
75% of transmission.
2. Sharing of unsterilized needles by intravenous drug
users and unsafe medical practices: 5-10% of
transmission.
3. Transfusions and Blood Products: Hemophiliac
population was decimated in 1980s. Risk is low
today. 3-5% of transmission.
4. Mother to Infant (Perinatal): 25% of children
become infected in utero, during delivery, or by
breast-feeding (with AZT only 3%). 5-10% of
transmission.
Perinatal Transmission of AIDS
Source: Tropical Medicine and Parasitology, 1997
Characteristics of all viruses
 Acellular
infectious agents
 Obligate intracellular parasites
 Possess either DNA or RNA, never both
 Replication is directed by viral nucleic acid
within a cell
 Do not divide by binary fission or mitosis
 Lack genes and enzymes necessary for energy
production
 Depend on host cell ribosomes, enzymes, and
nutrients for protein production
Unique Characteristics of HIV
 Retrovirus:
Unique enzyme reverse transcriptase,
converts viral RNA into DNA.
 Genetic material: 2 strands of RNA.
 Integrase: Inserts viral DNA into host DNA.
 Protease: Processes viral proteins. Essential for
maturation.
 Envelope with glycoproteins: Viral capsid is
covered by envelope derived from host cell
membrane.
Envelope contains a glycoprotein (gp120) which
attaches to CD4 receptor on host cell membrane.
 Coreceptors: Required for HIV infection.
CXCR4 and CCR5.
Structure of the Human Immunodeficiency Virus
HIV is a Retrovirus
Life Cycle of HIV
1. Attachment: Virus binds to surface molecule
(CD4) of T cells and macrophages.
 Coreceptors:
Required for HIV infection.
 CXCR4 and CCR5 mutants are resistant to infection.
2. Fusion: Viral envelope fuses with cell membrane,
releasing contents into the cell.
3. Reverse Transcription: Viral RNA is converted
into DNA by unique enzyme reverse transcriptase.
Reverse transcriptase
RNA ---------------------> DNA
Reverse transcriptase is the target of several HIV
drugs: AZT, ddI, and ddC.
HIV Life Cycle: Reverse Transcriptase
Converts RNA into DNA
Life Cycle of HIV
4. Integration: Viral DNA is inserted into host cell
chromosome by unique enzyme integrase.
Integrated viral DNA may remain latent for years
and is called a provirus.
5. Replication: Viral DNA is transcribed and RNA
is translated, making viral proteins.
Viral genome is replicated.
6. Assembly: New viruses are made.
7. Release: New viruses bud through the cell
membrane.
Course of HIV Infection
Definition of AIDS
AIDS is a syndrome: A collection of several diseases
and symptoms that differ from one individual to
another, but point to severe immunosuppression.
HIV Antibody positive and one of the following
(partial list):
Kaposi’s sarcoma
 Pneumocystis carinii pneumonia
 HIV dementia
 non-Hodgkin’s B cell lymphoma
 Yeast infection of esophagus, trachea, or lung
 Multiple bacterial infections in children <13 years
 Tuberculosis of the lung*
 Recurrent pneumonia*
 Invasive cervical carcinoma*
 All HIV+ persons with <200 CD4+ cells/ul*
*Added January 1, 1993.

AIDS Associated Disease Categories
1. Gastrointestinal: Cause most of illness and death
of late AIDS.
Symptoms:
 Diarrhea
 Wasting
(extreme weight loss)
 Abdominal
 Infections
pain
of the mouth and esophagus.
Pathogens: Candida albicans, cytomegalovirus,
Microsporidia, and Cryptosporidia.
African AIDS patient with slim disease
Source: Tropical Medicine and Parasitology, 1997
Opportunistic Oral Yeast Infection by
Candida albicans in an AIDS Patient
Source: Atlas of Clinical Oral Pathology, 1999
AIDS Associated Disease Categories
2. Respiratory: 70% of AIDS patients develop
serious respiratory problems.
Partial list of respiratory problems associated with AIDS:
 Bronchitis
 Pneumonia
 Tuberculosis
 Lung
cancer
 Sinusitis
 Pneumonitis
Chest X-Ray of AIDS Patient with Tuberculosis
AIDS Associated Disease Categories
3. Neurological: Opportunistic diseases and
tumors of central nervous system.
Symptoms many include: Headaches, peripheral
nerve problems, and AIDS dementia complex
(Memory loss, motor problems, difficulty
concentration, and paralysis).
AIDS Associated Disease Categories
4. Skin Disorders: 90% of AIDS patients develop
skin or mucous membrane disorders.
 Kaposi’s
sarcoma
• 1/3 male AIDS patients develop KS
• Most common type of cancer in AIDS patients
 Herpes
zoster (shingles)
 Herpes simplex
 Thrush
 Invasive cervical carcinoma
5. Eye Infections: 50-75% patients develop eye
conditions.
 CMV
retinitis
 Conjunctivitis
 Dry eye syndrome
Extensive tumor lesions of Kaposis’s sarcoma in AIDS patient.
Source: AIDS, 1997
Chronic Herpes Simplex infection with lesions on tongue and lips.
Source: Atlas of Clinical Oral Pathology, 1999.
Non-Hodgkin’s Lymphoma & ascites in AIDS patient
Source: Tropical Medicine and Parasitology, 1997
Drugs Against HIV
 Reverse
Transcriptase Inhibitors: Competitive
enzyme inhibitors. Example: AZT, ddI, ddC.
 Protease Inhibitors: Inhibit the viral proteases.
Prevent viral maturation.
 Problem with individual drug treatments:
Resistance.
 Drug Cocktails: A combination of:
 One
or two reverse transcriptase inhibitors
 One or two protease inhibitors.
 Drug
cocktails have been very effective in
suppressing HIV replication and prolonging the
life of HIV infected individuals, but long term
effectiveness is not clear.